1. Field of the Invention
The present invention relates to the fields of magnetic resonance imaging and contrast agents and disease diagnosis and treatment. More specifically, the invention relates to iron oxide nanoparticles that are either doped or not doped with varying amounts of metal ions and, optionally, gold-coated, and are surface-modified with a biomimetic and bioresponsive entity that imparts specificity of the contrast agent, which may include delivery of a therapeutic gene, to the desired target.
2. Description of the Related Art
In recent years, magnetic nanoparticles (MNPs) have generated significant interest within the scientific community due to their huge range of potential applications such as media materials for storage systems (1-2), biotechnology (3-4), magnetic separation (5-6) targeted drug delivery (7-8) and vehicles for gene and drug delivery (9-12). Among the various MNPs, undoped and transition metal-doped, e.g., Magnetite or Maghemite, iron oxide nanoparticles, Fe3O4, g-Fe2O3 and MxFeyOz have found many applications in the area of biomedical diagnostics and therapy.
In the field of imaging, the superparamagnetic nature of iron oxide nanoparticles enables their use as potential contrast agents for magnetic resonance imaging (MRI). These nanoparticles with very large magnetic susceptibilities strongly influence the T1 and T2 relaxation of water molecules surrounding these MRI contrast agents. In addition, the magnetic properties of these iron oxide nanoparticles are also dependent on particle size. Iron oxide nanoparticles that are below 15-20 nm retain superparamagnetism and influence the T2 relaxation to the largest extent (13-14). This influence on the T2 relaxation highly modulates the MRI properties of the iron oxide nanoparticles. Hence, by adjusting the core size of the nanoparticles the magnetic properties for MRI can be enhanced. Typically, MNPs are synthesized with a particle size of 10-500 nm in diameter for biomedical applications.
In addition to size, the biocompatibility, solubility, and monodispersity of these MNPs are also critical for their use in vivo (15). However, the surface-chemical properties of MNPs do not facilitate the conjugation of biomolecules. Therefore, the surface of these MNPs must undergo modification or functionalization to enable the chemistry needed for coupling biomolecules to MNPs. In other words, in order to make the magnetic nanoparticles efficient delivery vehicles, introduction of suitable functional groups onto the surface of the particle is essential so as to facilitate the conjugation of molecules that will increase its solubility and increase its availability for various conjugation processes. Also, the conjugation process has to be efficient, yielding a stable product, which does not compromise the activity of the biomolecules. Moreover, the signal of the nanoparticles for imaging or other analytical techniques should not be affected as a result of the conjugation. In addition, these nanoparticles should also have maximum surface area so as to facilitate the binding of a maximum number of linkage sites on the surface.
In the United States, breast cancer is second to lung cancer as the leading cause of cancer death in women. This year alone, ˜40,000 women will die from the disease despite a decline in the death rates. Detection is the best method to prevent mortality but only 60% of cancers are detected at the earliest, subclinical stages of the disease. Also, ovarian cancer has the highest mortality rate of all gynecological malignancies. Poor prognosis of the disease is directly related to late detection after peritoneal tumor dissemination and the formation of ascites. Failure to detect early primary tumors or metastases results in very poor clinical outcome.
MRI is a powerful imaging modality for detection of cancer and other diseases because it provides high spatial resolution and excellent soft tissue contrast. However, MRI imaging systems need to be developed that are sensitive enough to detect cancers in the early stage of development and to detect metastatic cancers.
Thus, there is a recognized need in the art for improved contrast agents effective to detect early stage primary and metastatic cancers via magnetic resonance imaging, including contrast agents suitable to deliver a therapeutic gene during imaging. More specifically, the prior art is deficient in biomimetic contrast agents and a dual functioning contrast agent/gene/drug delivery system effective to specifically target primary and metastatic cancer cells with MRI. The present invention fulfills this long-standing need and desire in the art.